Yaso Emmanuel

Regulation of human metabolism by hypoxia- inducible factor

The hypoxia-inducible factor (HIF) family of transcription factors directs a coordinated cellular response to hypoxia that includes the transcriptional regulation of a number of metabolic enzymes. Chuvash polycythemia (CP) is an autosomal recessive human disorder in which the regulatory degradation of HIF is impaired, resulting in elevated levels of HIF at normal oxygen tensions. Apart from the polycythemia, CP patients have marked abnormalities of cardiopulmonary function. No studies of integrated metabolic function have been reported. Here we describe the response of these patients to a series of metabolic stresses: exercise of a large muscle mass on a cycle ergometer, exercise of a small muscle mass (calf muscle) which allowed noninvasive in vivo assessments of muscle metabolism using 31P magnetic resonance spectroscopy, and a standard meal tolerance test. During exercise, CP patients had early and marked phosphocreatine depletion and acidosis in skeletal muscle, greater accumulation of lactate in blood, and reduced maximum exercise capacities. Muscle biopsy specimens from CP patients showed elevated levels of transcript for pyruvate dehydrogenase kinase, phosphofructokinase, and muscle pyruvate kinase. In cell culture, a range of experimental manipulations have been used to study the effects of HIF on cellular metabolism. However, these approaches provide no potential to investigate integrated responses at the level of the whole organism. Although CP is relatively subtle disorder, our study now reveals a striking regulatory role for HIF on metabolism during exercise in humans. These findings have significant implications for the development of therapeutic approaches targeting the HIF pathway.

A high-fat diet impairs cardiac high-energy phosphate metabolism and cognitive function in healthy human subjects

BACKGROUND High-fat, low-carbohydrate diets are widely used for weight reduction, but they may also have detrimental effects via increased circulating free fatty acid concentrations. OBJECTIVE We tested whether raising plasma free fatty acids by using a high-fat, low-carbohydrate diet results in alterations in heart and brain in healthy subjects. DESIGN Men (n = 16) aged 22 ± 1 y (mean ± SE) were randomly assigned to 5 d of a high-fat, low-carbohydrate diet containing 75 ± 1% of calorie intake through fat consumption or to an isocaloric standard diet providing 23 ± 1% of calorie intake as fat. In a crossover design, subjects undertook the alternate diet after a 2-wk washout period, with results compared after the diet periods. Cardiac (31)P magnetic resonance (MR) spectroscopy and MR imaging, echocardiography, and computerized cognitive tests were used to assess cardiac phosphocreatine (PCr)/ATP, cardiac function, and cognitive function, respectively. RESULTS Compared with the standard diet, subjects who consumed the high-fat, low-carbohydrate diet had 44% higher plasma free fatty acids (P < 0.05), 9% lower cardiac PCr/ATP (P < 0.01), and no change in cardiac function. Cognitive tests showed impaired attention (P < 0.01), speed (P < 0.001), and mood (P < 0.01) after the high-fat, low-carbohydrate diet. CONCLUSION Raising plasma free fatty acids decreased myocardial PCr/ATP and reduced cognition, which suggests that a high-fat diet is detrimental to heart and brain in healthy subjects.

Increasing plasma free fatty acids in healthy subjects induces aortic distensibility changes seen in obesity.

Background— Elevated free fatty acid (FFA) levels are known to impair aortic elastic function. In obesity, FFA levels are elevated and aortic distensibility (AD) reduced in a pattern that predominantly affects the distal aorta. Despite this, the role of FFAs in obesity-related aortic stiffness remains unclear. Methods and Results— Using vascular MRI, we aimed to determine if (1) FFA level correlated with AD in obesity; and (2) whether elevating FFA acutely and subacutely in normal-weight subjects reproduced the distal pattern of AD change in obesity. To do this, regional AD was recorded in 35 normal-weight and 70 obese subjects and then correlated with FFA levels. When compared with normal weight, obesity was associated with reduced AD in a pattern predominantly affecting the distal aorta (ascending aorta by −22%, proximal descending aorta by −25%, and abdominal aorta by −35%; P<0.001). After controlling for age, blood pressure, and body mass index, FFA levels remained negatively correlated with abdominal AD (r=−0.43, P<0.01). In 2 further normal-weight groups, AD was recorded before and after elevation of FFA levels with intralipid infusion (by +535%, n=9) and a 5-day high-fat, low-carbohydrate diet (by +48%, n=14). Conclusions— Both intralipid infusion and a low-carbohydrate diet resulted in reduced abdominal AD (infusion −22%, diet −28%; both P<0.05), reproducing the distal pattern AD reduction seen in obesity. These findings suggest that elevated FFA impair AD in obesity and provide a potential therapeutic target to improve aortic elastic function in obesity.

Reproducibility of 31P cardiac magnetic resonance spectroscopy at 3 T.

The purpose of this work was to take advantage of the new clinical field strength of 3 T to implement and optimize a chemical shift imaging (CSI) acquisition protocol to produce spectra of high quality with high specificity to the myocardium within a clinically feasible scan time. Further, an analysis method was implemented dependent purely on anatomical location of spectra, and as such free from any potential user bias caused by inference from spectral information. Twenty healthy male subjects were scanned on two separate occasions using the optimized CSI protocol at 3 T. Data were analyzed for intra‐ and inter‐subject variability, as well as intra‐ and inter‐observer variability. The average phosphocreatine (PCr)/adenosine triphosphate (ATP) value for scan 1 was 2.07 ± 0.38 and for scan 2 was 2.14 ± 0.46, showing no significant difference between scans. Intra‐subject variability was 0.43 ± 0.35 (percentage difference 20%) and the inter‐subject coefficient of variation was 18%. The intra‐observer variability, assessed as the absolute difference between analyses of the data by a single observer, was 0.14 ± 0.24 with no significant difference between analyses. The inter‐observer variability showed no significant differences between the PCr/ATP value measured by four different observers as demonstrated by an intra‐class correlation coefficient of 0.763. The increased signal available at 3 T has improved spatial resolution and thereby increased myocardial specificity without any significant decrease in reproducibility over previous studies at 1.5 T. We present an acquisition protocol that routinely provides high quality spectra and a robust analysis method that is free from potential user bias. Copyright

Human hippocampal energy metabolism is impaired during cognitive activity in a lipid infusion model of insulin resistance.

Neuronal glucose uptake was thought to be independent of insulin, being facilitated by glucose transporters GLUT1 and GLUT3, which do not require insulin signaling. However, it is now known that components of the insulin‐mediated glucose uptake pathway, including neuronal insulin synthesis and the insulin‐dependent glucose transporter GLUT4, are present in brain tissue, particularly in the hippocampus. There is considerable recent evidence that insulin signaling is crucial to optimal hippocampal function. The physiological basis, however, is not clear. We propose that while noninsulin‐dependent GLUT1 and GLUT3 transport is adequate for resting needs, the surge in energy use during sustained cognitive activity requires the additional induction of insulin‐signaled GLUT4 transport. We studied hippocampal high‐energy phosphate metabolism in eight healthy volunteers, using a lipid infusion protocol to inhibit insulin signaling. Contrary to conventional wisdom, it is now known that free fatty acids do cross the blood–brain barrier in significant amounts. Energy metabolism within the hippocampus was assessed during standardized cognitive activity. 31Phosphorus magnetic resonance spectroscopy was used to determine the phosphocreatine (PCr)‐to‐adenosine triphosphate (ATP) ratio. This ratio reflects cellular energy production in relation to concurrent cellular energy expenditure. With lipid infusion, the ratio was significantly reduced during cognitive activity (PCr/ATP 1.0 ± 0.4 compared with 1.4 ± 0.4 before infusion, P = 0.01). Without lipid infusion, there was no reduction in the ratio during cognitive activity (PCr/ATP 1.5 ± 0.3 compared with 1.4 ± 0.4, P = 0.57). This provides supporting evidence for a physiological role for insulin signaling in facilitating increased neuronal glucose uptake during sustained cognitive activity. Loss of this response, as may occur in type 2 diabetes, would lead to insufficient neuronal energy availability during cognitive activity.

Changes in Cardiac Substrate Transporters and Metabolic Proteins Mirror the Metabolic Shift in Patients with Aortic Stenosis

In the hypertrophied human heart, fatty acid metabolism is decreased and glucose utilisation is increased. We hypothesized that the sarcolemmal and mitochondrial proteins involved in these key metabolic pathways would mirror these changes, providing a mechanism to account for the modified metabolic flux measured in the human heart. Echocardiography was performed to assess in vivo hypertrophy and aortic valve impairment in patients with aortic stenosis (n = 18). Cardiac biopsies were obtained during valve replacement surgery, and used for western blotting to measure metabolic protein levels. Protein levels of the predominant fatty acid transporter, fatty acid translocase (FAT/CD36) correlated negatively with levels of the glucose transporters, GLUT1 and GLUT4. The decrease in FAT/CD36 was accompanied by decreases in the fatty acid binding proteins, FABPpm and H-FABP, the β-oxidation protein medium chain acyl-coenzyme A dehydrogenase, the Krebs cycle protein α-ketoglutarate dehydrogenase and the oxidative phosphorylation protein ATP synthase. FAT/CD36 and complex I of the electron transport chain were downregulated, whereas the glucose transporter GLUT4 was upregulated with increasing left ventricular mass index, a measure of cardiac hypertrophy. In conclusion, coordinated downregulation of sequential steps involved in fatty acid and oxidative metabolism occur in the human heart, accompanied by upregulation of the glucose transporters. The profile of the substrate transporters and metabolic proteins mirror the metabolic shift from fatty acid to glucose utilisation that occurs in vivo in the human heart.

Heart disease in pregnancy

Cardiac disease is the leading cause of maternal mortality in the developed world. The majority of women with heart disease are able to successfully undergo pregnancy. However, in women with severely impaired ventricular function, severe left heart obstruction, pulmonary hypertension and aortopathy, such as Marfan syndrome, with significant aortic dilatation, pregnancy is associated with a significant risk, and these women should be counselled against pregnancy if there is no option for treatment that reduces risk. Although there are increasing numbers of women with congenital heart disease who are considering pregnancy, as a result of joint expert specialist cardiac and obstetric care, maternal mortality is low. Most of the observed mortality occurs in women with structurally normal hearts who were not known to have heart disease before their pregnancy. It is therefore important that those caring for pregnant women are aware of the risk factors for and presentation of cardiac conditions in pregnancy. We review the presentation and management of both congenital and acquired heart diseases in pregnancy.

Outcomes of Patients With Hypoplastic Left Heart Syndrome Reaching Adulthood After Fontan Palliation: Multicenter Study

Hypoplastic left heart syndrome (HLHS) is a high-risk condition among the wider spectrum of single-ventricle physiology lesions, and few survivors have reached adulthood.1 As HLHS is one of the most common diagnoses for children undergoing Fontan palliation,2 identification of risk factors for adverse outcomes in this emerging population is of importance. We report results from a multicenter observational study that characterizes adults with Fontan palliation for underlying HLHS at entry into adulthood and defines factors associated with adverse outcomes. Adults (≥18 years by July 2014) with HLHS were studied. The diagnosis of HLHS was restricted to patients with mitral stenosis or atresia, aortic stenosis or atresia, and a diminutive left ventricle. Excluded were patients with other forms of dominant right ventricular lesions with univentricular physiology managed with a Norwood procedure (ie, unbalanced atrioventricular septal defect or double-outlet right ventricle) or those with heart transplantation. Available pediatric and adult cardiovascular data were reviewed. The primary end point (Fontan-specific major adverse cardiovascular event) was defined as death, transplantation listing, hospitalization (>24 hours) for heart failure requiring intravenous diuretics, sustained ventricular …

Late Peripheral Thoracic Aneurysms following Aortic Root Surgery in Patients with Loeys–Dietz Syndrome

The Loeys-Dietz syndrome is a multisystem connective tissue disorder characterized by aortopathy, arterial tortuosity, peripheral aneurysms, and skeletal features. The peripheral arteriopathy is an important cause of morbidity and potential mortality. This report presents 2 cases: the first demonstrating a 5-cm pseudoaneurysm of the right internal mammary artery and the second demonstrating a 2.3-cm aneurysm of the left internal mammary artery, each following aortic root surgery. These were successfully treated with percutaneous techniques. No complications were seen at follow-up as long as 2 years. Patients with Loeys-Dietzs syndrome require comprehensive long-term vascular follow-up and are likely to require percutaneous vascular interventions.

1046 Acute elevation of plasma free fatty acid levels reduces aortic distensibility

Introduction Decreased aortic distensibility (AD) is recognized in a range of different pathologies including hypertension, coronary artery disease, diabetes and obesity and has been proposed as an independent predictor of adverse outcomes. Studies in obesity show that the decrease in AD is most pronounced distally and is associated with elevated plasma free fatty acid (FFA) levels. Acute elevation of plasma FFA levels has been shown to reduce peripheral arterial compliance, but the effect on central AD in normal weight subjects is unknown. Our hypothesis was that elevations in plasma FFA levels would reduce AD in a pattern similar to that seen in obesity.